Immune Modulators for Treating COVID-19

Covid19 Clinical Trial

— ACTIV-1 IM  

Official title:

Randomized Master Protocol for Immune Modulators for Treating COVID-19

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04593940
• Other study ID #: Pro00106301
• Status: Completed
• Phase: Phase 3
• Start date: October 15, 2020
• Est. completion date: March 5, 2022

Study information

• Verified date: September 2023
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

ACTIV-1 IM is a master protocol designed to evaluate multiple investigational agents for the treatment of moderately or severely ill patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The research objectives are to evaluate each agent with respect to speed of recovery, mortality, illness severity, and hospital resource utilization. Each agent will be evaluated as add-on therapy to the standard of care (SoC) in use at the local clinics, including remdesivir (provided). The SoC may change during the course of the study based on other research findings. Comparisons of the agents among themselves is not a research objective.

The study population corresponds to moderately and severely ill patients infected with the coronavirus disease 2019 (COVID-19) virus. Recruitment will target patients already hospitalized for treatment of COVID-19 infection as well as patients being treated for COVID-19 infection in Emergency Departments while waiting to be admitted to the hospital. Patients both in and out of the ICU are included in the study population.

Description:

ACTIV-1 IM is a master protocol designed to evaluate immune modulators for the treatment of moderately or severely ill hospitalized patients infected with COVID-19. Trial participants will be assessed daily while hospitalized. If the participants are discharged from the hospital prior to Day 29, they will have follow-up study visits at Days 8, 11, 15, 22, and

29. For discharged participants, it is preferred that the Day 8, 11, 15, and 29 visits are in person to obtain safety laboratory tests and blood (serum/plasma) samples for secondary research as well as clinical outcome data. However, infection control or other restrictions may limit the ability of the participant to return to the clinic. In this case, these visits may be conducted by phone, and only clinical data will be obtained. The Day 22 visit does not have laboratory tests or collection of samples and is conducted by phone. The Day 60 assessment will be conducted by phone.

The effectiveness of each therapeutic agent as add-on therapy to SoC plus remdesivir (provided) will be evaluated based on the primary endpoint of time to recovery by Day 29. The sample size requirements are based on the ability to detect a moderate improvement in time to recovery (3-4 fewer days) for each agent. A total of 788 recoveries are required for each comparison to provide approximately 85% power to detect a recovery rate ratio of 1.25. Assuming 73% of participants achieve recovery in 28 days, consistent with the ACTT-1 results, the total sample size to evaluate 1, 2, and 3 agents in ACTIV-1 IM is approximately 1080, 1620, and 2160, respectively. Because each agent is being compared to SoC with no between-agent comparisons, no multiplicity adjustments for multiple agents are planned.

The CVC arm of the study was closed to enrollment on 3-Sep-2021.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1971
• Est. completion date: March 5, 2022
• Est. primary completion date: January 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Admitted to a hospital or awaiting admission in the ED with symptoms suggestive of COVID-19.

2. Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures.

3. Subject (or legally authorized representative) understands and agrees to comply with planned study procedures.

4. Male or non-pregnant female adults =18 years of age at time of enrollment.

5. Has laboratory-confirmed (within 14 days prior to enrollment) SARS-CoV-2 infection as determined by PCR or other commercial or public health assay in any specimen.

6. Ongoing illness of any duration, and at least one of the following:

• Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR

• Blood oxygen saturation (SpO2) =94% on room air, OR

• Requiring supplemental oxygen, OR

• Requiring mechanical ventilation or ECMO.

7. Women of childbearing potential must agree to either abstinence or use of at least one primary form of contraception not including hormonal contraception from the time of screening through Day 60.

8. Agrees to not to participate in another interventional trial for the treatment of COVID-19 through Day 60.

Exception 1: Participant may co-enroll in ACTIV-4 (ACTIV-4A and ACTIV-4C). Exception 2:

Participants in ACTIV-2 who have been hospitalized may be enrolled in ACTIV-1 as long as ACTIV-2 study therapy has been discontinued. They will remain in ACTIV-2 follow-up.

Exception 3: If participant is already participating in a COVID-19 vaccine trial but develops COVID-19 disease that requires hospitalization, participant is eligible for this study, assuming all other inclusion/exclusion criteria are met.

Exclusion Criteria:

1. ALT or AST >10 times the upper limit of normal.

2. Estimated glomerular filtration rate (eGFR) <30 mL/min (including patients receiving hemodialysis or hemofiltration).

Exception: Participants with an eGFR <30 mL/min may enroll as long as their renal insufficiency has been stable without renal replacement therapy for =1 month and they are not current candidates for renal replacement therapy. These participants will not receive remdesivir.

3. Neutropenia (absolute neutrophil count <1000 cells/µL) (<1.0 x 103/µL or <1.0 GI/L).

4. Lymphopenia (absolute lymphocyte count <200 cells/µL) (<0.20 x 103/µL or <0.20 GI/L)

5. Pregnancy or breast feeding.

6. Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours.

7. Known allergy to any study medication.

8. Received cytotoxic or biologictargeted immune-modulator treatments (such as anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab], anti-IL-17, or T-cell or B-cell targeted therapies ([e.g., rituximab), tyrosine kinase], JAK inhibitors [including baricitinib,], TNF inhibitors, or interferon) within 4 weeks or 5 half-lives prior to screening., whichever is longer. Steroid dependency, defined as need for prednisone at a dose >10 mg (or equivalent) for >1 month within 2 weeks of screening, is exclusionary. Note Exception 1: Dexamethasone (at a dose of 6 mg per day for up to 10 days) is permitted for the treatment of COVID-19 in patients who are already mechanically ventilated and in patients who require supplemental oxygen at screening, but who are not mechanically ventilated in accordance with national guidelines. Note Exception 2: Infusion of convalescent plasma given for treatment of COVID-19 while on-study is also allowed.

Exception 3: Monoclonal antibody therapy given for COVID-19 treatment at any time prior to enrollment is also allowed.

9. BasedKnown or suspected history of untreated tuberculosis (TB). TB diagnosis may be suspected based on medical history and concomitant therapies that would suggest TB infection, have suspected clinical diagnosis of current active tuberculosis (TB) or, if. Participants are also excluded if they have known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by history only, no screening required).

10. Based on medical history and concomitant therapies that would suggest infection,Known or suspected serious, active bacterial, fungal, or viral (infection (excepting SARS-CoV-2 and including, but not limited to, active HBV, HCV, or HIV/AIDS). with the latter defined as a CD4 count <200 or an unsuppressed HIV viral load), or other infection (besides COVID-19) that in the opinion of the investigator could constitute a risk when taking investigational product.

Note: Broad-spectrum empiric antibiotic usage does not exclude participation.

11. Have received any live vaccine (that is,or live attenuated) within 3 months before screening, or intend to receive a live vaccine (or live attenuated) during the study. Note Exception: Use of prior non-live (inactivated) vaccinations is allowed for all participants, including any vaccine for COVID-19.

12. Severe hepatic impairment (defined as liver cirrhosis Child stage C).

13. CurrentKnown severe heart failure (New York Heart Association [NYHA] III-IV).) or new-onset left-systolic or global cardiac dysfunction in the setting of COVID-19.

Exception: Right-sided heart dysfunction or pulmonary hypertension thought related to COVID-19 is permitted.

14. In the Investigator's judgment, the patient has any advanced organ dysfunction that would not make participation appropriate.

Related Conditions & MeSH terms

• COVID-19
• Covid19

Intervention

Drug:
• Infliximab
study drug or matching placebo
• Abatacept
study drug or matching placebo
• Remdesivir
Standard of Care
• cenicriviroc (closed to enrollment as of 3-Sep-2021)
study drug or matching placebo

Locations

Country	Name	City	State
Argentina	Hospital Interzonal Dr Jose Penna Bahia Blanca	Bahía Blanca	Buenos Aires
Argentina	Hospital Ramos Mejia	Buenos Aires
Argentina	Sanatorio Ramon Cereijo	Caba	Buenos Aires
Argentina	Hospital Rawson	Cordoba
Argentina	Sanatorio Allende	Córdoba
Argentina	Instituto Medico Platense	La Plata	Buenos Aires
Argentina	Sanatorio Britanico	Rosario
Argentina	Sanatorio Diagnóstico/ Instituto del Buen Aire	Santa Fe
Argentina	Clinica Central S.A.	Villa Regina	Rio Negro
Brazil	Hospital Felício Rocho	Belo Horizonte	MG
Brazil	Hospital Brasília	Brasília	DF
Brazil	Hospital e Maternidade Celso Pierro - PUC Campinas	Campinas	São Paulo/SP
Brazil	Hospital de Clinicas de Porto Alegre HCPA	Porto Alegre	Rio Grande Do Sul / RS
Brazil	Hospital Ernesto Dornelles	Porto Alegre	Rio Grande D Sul /RS
Brazil	Santa Casa de Misericordia de Porto Alegre	Porto Alegre	Rio Grande Do Sul/RS
Brazil	Instituto DOR de Ensino e Pesquisa Hospital Glória D'Or	Rio De Janeiro	Rio De Janeiro / RJ
Mexico	Nuevo Hospital Civil de Guadalajara "Dr. Juan I. Menchaca"	Guadalajara	Guadalajara Jalisco
Mexico	Hospital Universitario "Dr. Jose Eleuterio Gonzalez"	Nuevo León	Monterrey
Peru	Hospital Regional Lambayeque	Chiclayo
Peru	Hospital Central FAP	Lima	Lima/Lima
Peru	Hospital de Chancay y Servicios Basicos de Salud	Lima
Peru	Hospital Nacional Aezobispo Loayza	Lima
Peru	Hospitala Nacional Hipólito Unánue	Lima
Peru	Clínica Belén SANNA	Piura
United States	MidMichigan Medical Center- Gratiot	Alma	Michigan
United States	Anne Arundel Medical Center	Annapolis	Maryland
United States	Johns Hopkins Medical Center	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Boston Medical Center	Boston	Massachusetts
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	NYU Brooklyn	Brooklyn	New York
United States	University at Buffalo	Buffalo	New York
United States	University of North Carolina - Chapel Hill	Chapel Hill	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	University of Illinois at Chicago	Chicago	Illinois
United States	University of Missouri Health Care	Columbia	Missouri
United States	Methodist Health System Clinical Research Institute	Dallas	Texas
United States	Duke University	Durham	North Carolina
United States	Trinitas Hospital	Elizabeth	New Jersey
United States	Flushing Hospital Medical Center	Flushing	New York
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	University of Texas Health Science Center - Houston	Houston	Texas
United States	University of Iowa	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	University of Florida-Jacksonville	Jacksonville	Florida
United States	Jamaica Hospital Medical Center	Jamaica	New York
United States	University of Kansas	Kansas City	Kansas
United States	University of Tennessee Medical Center	Knoxville	Tennessee
United States	Gundersen Health System	La Crosse	Wisconsin
United States	Scripps Clinical Medical Group	La Jolla	California
United States	University of Kentucky	Lexington	Kentucky
United States	University of Arkansas Medical Sciences	Little Rock	Arkansas
United States	NYU Long Island	Long Island City	New York
United States	UCLA - Ronald Reagan Medical Center	Los Angeles	California
United States	Loyola University Medical Center	Maywood	Illinois
United States	MidMichigan Medical Center - Midland	Midland	Michigan
United States	Riverside University	Moreno Valley	California
United States	West Virginia University	Morgantown	West Virginia
United States	Rutgers New Jersey Medical School	New Brunswick	New Jersey
United States	Ochsner Medical Center	New Orleans	Louisiana
United States	Tulane School of Medicine	New Orleans	Louisiana
United States	University Medical Center New Orleans	New Orleans	Louisiana
United States	Harlem Hospital Center	New York	New York
United States	New York University Langone Medical Center	New York	New York
United States	Weill Cornell Medicine	New York	New York
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	UC Irvine Medical Center	Orange	California
United States	Stanford University Medical Center	Palo Alto	California
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	Banner University Medical Center	Phoenix	Arizona
United States	Oregon Health and Science University	Portland	Oregon
United States	St Lawrence Health System	Potsdam	New York
United States	Virginia Commonwealth University Medical Center	Richmond	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Rochester Medical Center-Strong Memorial Hospital	Rochester	New York
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of Utah	Salt Lake City	Utah
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	UCLA Medical Center- Santa Monica	Santa Monica	California
United States	University of Washington Medical Center	Seattle	Washington
United States	Avera McKennan Hospital	Sioux Falls	South Dakota
United States	Providence Medical Research Center	Spokane	Washington
United States	Mercy Saint Vincent Medical Center	Toledo	Ohio
United States	Trinity Mother Frances Hospital	Tyler	Texas
United States	University of Texas Health Center at Tyler	Tyler	Texas
United States	Medstar Washington Hospital Center	Washington	District of Columbia
United States	Wake Forest University	Winston-Salem	North Carolina
United States	U Mass Memorial Medical Center	Worcester	Massachusetts
United States	U Mass University Medical Center	Worcester	Massachusetts
United States	Reading Hospital Study	Wyomissing	Pennsylvania

Sponsors (3)

Lead Sponsor	Collaborator
Daniel Benjamin	Biomedical Advanced Research and Development Authority, National Center for Advancing Translational Sciences (NCATS)

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Mexico,  Peru, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants Who Had Recovered by Day 28	Time to recovery by day 28. The number of participants who have recovered by day 28.	Days 1-28
Secondary	Number of Participants With Clinical Status for Day 14 Using an 8 Point Ordinal Scale	8-point ordinal scale assessing clinical status (1=Death is worst, 8=not hospitalized/no limitations on activities is best) To determine a participant's clinical status using the ordinal scale their clinical status was collected at Day 15 assessing day 14.; The scale used in this study is as follows (from worst to best): Death; Hospitalized, on invasive mechanical ventilation or ECMO; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, requiring supplemental oxygen; Hospitalized, not requiring supplemental oxygen - requiring ongoing medical in-patient care (COVID-19 related or otherwise); Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical in-patient care; This would include those kept in hospital for quarantine/infection control/social reasons, awaiting bed in rehabilitation facility or homecare, etc.; Not hospitalized, limitation on activities and/or requiring home oxygen; Not hospitalized,	Day 14
Secondary	Mortality Through 28 Days	mortality at day 28	Day 1-28
Secondary	Number of Participants With Clinical Status for Day 28 Using an 8 Point Ordinal Scale	8-point ordinal scale assessing clinical status (1=Death is worst, 8=not hospitalized/no limitations on activities is best) To determine a participant's clinical status using the ordinal scale their clinical status was collected at Day 29 assessing day 28.; The scale used in this study is as follows (from worst to best): Death; Hospitalized, on invasive mechanical ventilation or ECMO; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, requiring supplemental oxygen; Hospitalized, not requiring supplemental oxygen - requiring ongoing medical in-patient care (COVID-19 related or otherwise); Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical in-patient care; This would include those kept in hospital for quarantine/infection control/social reasons, awaiting bed in rehabilitation facility or homecare, etc.; Not hospitalized, limitation on activities and/or requiring home oxygen; Not hospitalized,	Day 28
Secondary	Mortality Through 14 Days	mortality at day 14	Day 1-14
Secondary	Number of Participants Who Met a One Point Improvement in One Category From Day 0 (Baseline) to Day 28 Using an 8-point Ordinal Scale	8-point ordinal scale assessing clinical status (1=Death is worst, 8=not hospitalized/no limitations on activities is best). Number of people who met a 1 point improvement.; The scale used in this study is as follows (from worst to best): Death; Hospitalized, on invasive mechanical ventilation or ECMO; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, requiring supplemental oxygen; Hospitalized, not requiring supplemental oxygen - requiring ongoing medical in-patient care (COVID-19 related or otherwise); Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical in-patient care; This would include those kept in hospital for quarantine/infection control/social reasons, awaiting bed in rehabilitation facility or homecare, etc.; Not hospitalized, limitation on activities and/or requiring home oxygen; Not hospitalized, no limitations on activities.	Day 1-day 28
Secondary	Number of Participants Who Met a One Point Improvement in Two Categories From Day 0 (Baseline) to Day 28 Using an 8-point Ordinal Scale	8-point ordinal scale assessing clinical status (1=Death is worst, 8=not hospitalized/no limitations on activities is best). Number of people who met a two category improvement.; The scale used in this study is as follows (from worst to best): Death; Hospitalized, on invasive mechanical ventilation or ECMO; Hospitalized, on non-invasive ventilation or high flow oxygen devices; Hospitalized, requiring supplemental oxygen; Hospitalized, not requiring supplemental oxygen - requiring ongoing medical in-patient care (COVID-19 related or otherwise); Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical in-patient care; This would include those kept in hospital for quarantine/infection control/social reasons, awaiting bed in rehabilitation facility or homecare, etc.; Not hospitalized, limitation on activities and/or requiring home oxygen; Not hospitalized, no limitations on activities.	Day 1- day 28
Secondary	Mean Change in the 8-point Ordinal Scale From Day 0 to Day 2	8-point ordinal scale assessing clinical status (1=Death is worst, 8=not hospitalized/no limitations on activities is best)	Day 0 to day 2
Secondary	Mean Change in the 8-point Ordinal Scale From Day 0 to Day 4	8 point ordinal scale assessing clinical status (1=death is worst, 8=not hospitalized/no limitations on activities is best)	Day 0 to day 4
Secondary	Mean Change in the 8-point Ordinal Scale From Day 0 to Day 7	8-point ordinal scale assessing clinical status (1=death is worst, 8=not hospitalized/no limitations on activities=best)	Day 0 to day 7
Secondary	Mean Change in the 8-point Ordinal Scale From Day 0 to Day 10	8-point ordinal scale assessing clinical status (1=death is worst, 8=not hospitalized/no limitations on activities is best)	Day 0 to day 10
Secondary	Mean Change in the 8-point Ordinal Scale From Day 0 to Day 14	8-point ordinal scale assessing clinical status (1=death is worst, 8=not hospitalized/no limitations on activities is best)	Day 0 to day 14
Secondary	Mean Change in the 8-point Ordinal Scale From Day 0 to Day 21	8-point ordinal scale assessing clinical status (1=death is worst, 8=not hospitalized/no limitations on activities is best)	Day 0 to day 21
Secondary	Mean Change in the 8-point Ordinal Scale From Day 0 to Day 28	8-point ordinal scale assessing clinical status (1=death is worst, 8=not hospitalized/no limitations on activities is best)	Day 0 to day 28
Secondary	Duration (Days) Alive and Free of Supplemental Oxygen	Days alive and free of supplemental oxygen	Day 1 to day 28
Secondary	Number of Patients With New Supplemental Oxygen Use	Number of patients with new supplemental oxygen use	Day 1-day 28
Secondary	Duration (Days) Alive and Free of Non-invasive Ventilation/ High Flow Oxygen	Days alive and free of non-invasive ventilation/ high flow oxygen	Day 1 to day 28
Secondary	Number of Patients With New Non-invasive Ventilation/High Flow Oxygen Use	Number of patients with new non-invasive ventilation/high flow oxygen use	Day 1-day 28
Secondary	Duration (Days) Alive and Free of Invasive Mechanical Ventilation or ECMO	Days alive and free of invasive mechanical ventilation or ECMO	Day 1 to day 28
Secondary	Number of Patients With New Mechanical Ventilation or ECMO Use	Number of patients with new mechanical ventilation or ECMO use	Day 1 to day 28
Secondary	Duration (Days) Alive and Out of the Hospital	Days alive and out of the hospital	Through day 28
Secondary	Number of Patients With SAEs Through Day 28	Cumulative Incidence of SAEs through day 28	Day 28
Secondary	Number of Patients With Grade 3 and 4 Adverse Events	Cumulative incidence of adverse events of grade 3 and 4	Day 28
Secondary	Number of Patients With Adverse Events Leading to Dose Modification	Number of patients with adverse events (serious and non serious) leading to dose modification	Day 1-28